This randomized pilot clinical trial studies pazopanib hydrochloride followed by chemotherapy and surgery in treating patients with soft tissue sarcoma. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes that are needed for cell growth and may also stop the growth of soft tissue sarcoma by blocking blood flow to the tumor. Giving pazopanib hydrochloride and chemotherapy before surgery may make the tumor smaller and reduce the amount of tissue that needs to be removed.

Absolute values and changes in maximum SUV of tumors measured by FDG-PET pre- and post receipt of pazopanib versus placebo, and post receipt of 2 courses of preoperative chemotherapy [ Time Frame: At baseline and 14 days ] [ Designated as safety issue: No ]

Comparison will likely be conducted using a two-sided Wilcoxon rank sum test, often used as a nonparametric alternative to the two-sample t-test for studies with a small sample size.

Tumor response by RECIST criteria [ Time Frame: At 14 days ] [ Designated as safety issue: No ]

RECIST measurements will be performed on serial MRIs to evaluate the correlation with FDG-PET. The longest diameter (LD) of the target lesions will be measured and reported as the baseline LD. The baseline LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.

Correlation of pazopanib hydrochloride trough concentration with the change in SUV from FDG PET and change in RECIST measurements on MRIs [ Time Frame: At 14 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Safety profile of sequential treatment with pazopanib and pre-operative chemotherapy with doxorubicin and ifosfamide [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]

All reported adverse events will be coded using the Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria. Listings will be provided for all on-study deaths and adverse events that lead to withdrawal from study. Narratives of all serious adverse events and deaths on-study will be provided. The number and percent of subjects reporting adverse events (all, severe or worse, serious and related) will be quantified.

Pathologic response at the time of surgery as measured by % tumor viability [ Time Frame: An expected average of 12 weeks ] [ Designated as safety issue: No ]

Estimate the amount of viable tumor, and report the percentage of necrosis. For purpose of analysis, tumors will be classified as either >= 95% necrosis or < 95% necrosis.

Progression free survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Defined as the duration of time from randomization to progressive disease (per RECIST), local recurrence, distant metastatic disease (exclusive of stage IV subjects), or death, whichever occurs first.

Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Defined as the interval of time from randomization until death from any cause.

Change in plasma and tumor angiogenic biomarker levels pre- and post neoadjuvant therapy [ Time Frame: At baseline and after 14 days ] [ Designated as safety issue: No ]

Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.

Drug: Pazopanib Hydrochloride

Given PO

Other Names:

GW786034B

Votrient

Drug: Doxorubicin Hydrochloride

Given IV

Drug: Ifosfamide

Given IV

Procedure: Therapeutic Conventional Surgery

Undergo surgery

Radiation: External Beam Radiation Therapy

Undergo external beam radiation therapy

Other Names:

Definitive Radiation Therapy

EBRT

External Beam Radiation Therapy

External Beam RT

Other: Pharmacological Study

Correlative studies

Other Name: pharmacological studies

Other: Laboratory Biomarker Analysis

Correlative studies

Placebo Comparator: Arm II (placebo)

Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.

Drug: Doxorubicin Hydrochloride

Given IV

Drug: Ifosfamide

Given IV

Other: Placebo

Given PO

Other Name: PLCB

Procedure: Therapeutic Conventional Surgery

Undergo surgery

Radiation: External Beam Radiation Therapy

Undergo external beam radiation therapy

Other Names:

Definitive Radiation Therapy

EBRT

External Beam Radiation Therapy

External Beam RT

Other: Pharmacological Study

Correlative studies

Other Name: pharmacological studies

Other: Laboratory Biomarker Analysis

Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the absolute values and changes in standardized uptake values (SUV) by fludeoxyglucose F18 (FDG)-positron emission tomography (PET) before and after a 14 day Run-in period of pazopanib (pazopanib hydrochloride) versus placebo, and to compare this to the change in SUV following pre-operative chemotherapy.

II. To evaluate the correlation between antiangiogenic activity and pazopanib drug exposure.

III. To assess the response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria after the 14 day Run-in period of pazopanib versus placebo and compare this to the response rate following pre-operative chemotherapy.

SECONDARY OBJECTIVES:

I. To examine the activity of antiangiogenic therapy with pazopanib combined with pre-operative chemotherapy for high risk extremity soft tissue sarcomas as measured by: histological necrosis at surgery; change in plasma and tumor biomarker assays of angiogenesis

II. To evaluate the safety of sequential treatment with pazopanib and pre-operative chemotherapy with doxorubicin (doxorubicin hydrochloride) and ifosfamide.

All patients then receive neoadjuvant chemotherapy comprising doxorubicin hydrochloride intravenously (IV) continuously over days 1-3 and ifosfamide IV on days 1-5. Treatment repeats every 21 days for 4 courses. Beginning 2-4 weeks later, all patients undergo surgery followed by 2 more courses of chemotherapy 2-4 weeks after completion of surgery. Some patients may also undergo adjuvant external beam radiation therapy 5 days a week for 5 days followed by a boost. Patients treated on Arm I may resume pazopanib hydrochloride 1 week after completion of all adjuvant therapy for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Measurable disease greater than 5 centimeters in greatest dimension; measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be recorded) by chest x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI) or with calipers by clinical exam; all tumor measurements must be recorded in millimeters (or decimal fractions of centimeters)

Intermediate or high grade lesions: 2 or 3 on a scale of 1-3 or grades 2 to 4 on a scale of 1-4

Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities or on the body wall

Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) within 1.2 X the ULN unless a subject is receiving Coumadin and has stable INR which is in range for the desired level of anticoagulation

Left ventricular ejection fraction (LVEF) >= 50%

Blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings on baseline assessment prior to enrollment is less than 140/90 mmHg

Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib will be determined following review of their cases by the Principal Investigator

Women of child-bearing potential and men must agree to use adequate contraception

A female is eligible to enter and participate in this study if she is of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) or if she is of childbearing potential

Ability to understand and the willingness to sign a written informed consent document

Subjects with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or other agents used in the study

Subjects who have both bilirubin > ULN and AST/ALT > ULN

Subjects with a urine protein/creatinine ratio greater than 1

Subjects with a baseline corrected QT (QTc) of equal to or greater than 480 msecs or other significant electrocardiogram (ECG) abnormalities

Certain medications that act through the cytochrome P450 (CYP450) system are specifically prohibited in subjects receiving pazopanib and others should be avoided or administered with extreme caution and require principal investigator (PI) approval

Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib

Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are prohibited

Medications which have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution

Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2, or CYP2C19 in vivo but does in vitro; therefore, therapeutic doses of warfarin, a substrate of CYP2C9, and omeprazole, a substrate of CYP2C19 are permitted; caffeine, a substrate of CYP1A2, is also permitted

Certain medications that are associated with a risk for QTc prolongation and/or Torsades de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible

Subjects who require heparin other than low-molecular weight heparin

Subjects with any condition that may impair the ability to swallow or absorb oral medications/investigational product including:

Any lesion, whether induced by tumor, radiation or other conditions, which makes it difficult to swallow capsules or pills

Prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel

Active peptic ulcer disease, not on a proton pump inhibitor

Malabsorption syndrome

Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including

Other gastrointestinal conditions which increase the risk of perforation

History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to beginning study treatment

Subjects with any of the following cardiovascular conditions within the past 6 months:

Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

Cardiac arrhythmia

Admission for unstable angina

Cardiac angioplasty or stenting

Coronary artery bypass graft surgery

Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks

Arterial thrombosis

Symptomatic peripheral vascular disease

Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; a subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible

History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to first dose of study drug

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01446809